CN115813855A

CN115813855A - Low-concentration atropine medicine product and preparation method thereof

Info

Publication number: CN115813855A
Application number: CN202310054194.2A
Authority: CN
Inventors: 刘晔; 张在娟; 崔司琪; 李卫杰; 赵江平; 郑昕
Original assignee: Suzhou Aokangweishi Biotechnology Co ltd
Current assignee: Suzhou Aokangweishi Biotechnology Co ltd
Priority date: 2023-02-03
Filing date: 2023-02-03
Publication date: 2023-03-21
Also published as: CN118178315A; WO2024160252A1; WO2024159979A1

Abstract

A low concentration atropine pharmaceutical product and method of manufacture thereof, the product comprising a packaging container having a dual cavity, and a first cavity and a second cavity of a communicable sealed design; the first liquid medicine is placed in the first cavity, and the second liquid medicine is placed in the second cavity; when the medical liquid mixing device is used, the double cavities are communicated by destroying the sealing structure between the first cavity and the second cavity, so that the first medical liquid and the second medical liquid are mixed into a mixed medical liquid; the mixed liquid medicine comprises: 0.005 to 0.2 percent of active ingredient; 0 to 3.5 percent of buffer system; osmotic pressure regulator 0~5%; the balance being water. The invention combines the atropine with low concentration with a novel packaging container, the main drug end only contains the atropine and buffer solution, the diluting end contains the buffer solution and osmotic pressure regulator, and the main drug solution and the diluting solution are uniformly mixed when in use, thereby not only ensuring the stability of the atropine with low concentration, but also ensuring the sterility and comfort of use.

Description

Low-concentration atropine pharmaceutical product and preparation method thereof

Technical Field

The invention relates to the field of manufacturing of medicine products, in particular to an atropine medicine product with low concentration and a manufacturing method thereof.

Background

Atropine is an anticholinergic agent, an M-receptor blocker. The small dose of atropine can block the combination of acetylcholine or cholinomimetic and M receptor, and play an antagonistic role, and has low selectivity to different M receptor subtypes.

Researches prove that atropic medicaments are the most effective medicaments for preventing the myopia progression of teenagers and children at present, but the atropic medicaments with high concentration have many adverse reactions and side effects, and bring harm and potential safety hazard to the health of the teenagers and children. In terms of photophobia, 100% of 1% of atropine patients found to be photophobic in Yen et al studies, and 22% of 0.5% of atropine patients found to be photophobic in Shih et al studies. In the ATOM1 study, 34 patients (17%) were abandoned because of intolerable side effects with 1% atropine.

Since high concentrations of atropine drugs are associated with many adverse effects and side effects, there have been groups that have begun to investigate low concentrations of atropine drugs, such as: clinical studies with atorin at low concentrations of 0.5%, 0.1%, 0.01% from ATOM 2 revealed that 0.015% atropine was effective in controlling the progression of myopia in patients, with only 1 case showing near-sightedness and mild anaphylaxis, with significantly less than 0.5% and 0.1% effect on pupil dilation and patient accommodation. Both 0.05% and 0.01% atropine of the research team Jason C, et al, university of Chinese, hong Kong, did not exhibit visual related side effects, and the former was found to have a better myopia control effect.

The low-concentration atropine has already been developed in stages for treating juvenile myopia, but the low-concentration atropine solution has poor stability, is sensitive to light and is easy to hydrolyze under alkaline conditions. Therefore, the stability of the atropine with low concentration is ensured, and the atropine has larger development space and value in the field of ophthalmology.

The eye drops prepared from the atropine with low concentration have wide market prospect and can effectively treat the myopia development of teenagers and children. Currently, atropine dosage forms are marketed in china: tablets, injections, eye ointments, eye gels, etc., eye drops (concentration of 1%) are marketed in the united states, but not in china.

In the patents published in China at present, most atropine eye drops are packaged in multiple doses and contain preservatives, so that the eye drops can cause damage to the eye surface if being used by teenagers for a long time. Such as: patent CN113662915A discloses an eye mixed liquid medicine containing atropine sulfate, wherein the pH threshold of the composition is 3.5-4.0; an atropine sulfate eye drop is disclosed in patent CN111840221A, wherein the pH of the eye drop is =4.5-5.5; an atropine-containing aqueous composition having a pH in the range of 6 or below 6 is disclosed in patent CN109310687 a; in patent CN110833526B, an ophthalmic preparation for preventing and treating juvenile myopia and a preparation method thereof are protected, wherein the pH threshold range of components of the ophthalmic composition is between 4.5 and 5.5; patent CN111803441A discloses sodium hyaluronate eye drops containing 0.01% atropine and a preparation method thereof, wherein the pH threshold of the eye drops is 4.5-6.

In the technical scheme of the atropine eye drops disclosed in the patent, the pH threshold of the final composition is below 6 or 6, and the pH value is not proper for human eyeball organs, so that certain irritation exists. The technical problems that the low-concentration atropine solution has poor stability, is sensitive to light and is easy to hydrolyze under alkaline conditions are not solved. Further, many of the above patents also mention the use of bacteriostatic or preservative agents, and thus may cause certain side effects after use.

Therefore, the problem to be solved by the present invention is to provide a low concentration atropine eye drop composition which has a pH closer to the appropriate range of human eye organs, contains no preservative, has good storage stability, and is simple in structure and preparation process.

Disclosure of Invention

The invention aims to provide an atropine drug product with low concentration and a manufacturing method thereof.

In order to achieve the purpose, the technical scheme adopted by the invention on the product level is as follows:

a low concentration atropine pharmaceutical product comprising:

the packaging container is provided with a double cavity, and the first cavity and the second cavity are of a communicated sealing design;

further comprising:

a first liquid medicine placed in the first cavity, and a second liquid medicine placed in the second cavity;

when the medical liquid mixing device is used, the double cavities are communicated by destroying the sealing structure between the first cavity and the second cavity, so that the first medical liquid and the second medical liquid are mixed into a mixed medical liquid;

the mixed liquid medicine comprises:

0.005-0.2% of active component;

0 to 3.5 percent of buffer system;

0 to 5 percent of osmotic pressure regulator;

the balance of water;

the above units are mass percentages.

According to a further technical scheme, the active ingredient comprises atropine or pharmaceutically acceptable salts thereof; the buffer system is selected from one or more of citric acid, sodium citrate, boric acid, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate.

According to a further technical scheme, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and glucose. According to a further technical scheme, the mixed liquid medicine comprises:

0.005-0.2% of atropine or pharmaceutically acceptable salt thereof;

0 to 0.09 percent of citric acid;

0 to 0.45 percent of sodium citrate;

0 to 0.9 percent of sodium chloride;

the balance of water;

the above units are mass percentages.

In a further aspect, the first medical fluid comprises:

0.01 to 0.4 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

the second liquid medicine comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

0 to 1.8 percent of sodium chloride;

the balance of water;

the above units are mass percentages;

wherein the mass ratio of the first liquid medicine to the second liquid medicine is 0.8-1: 1. in a further aspect, the first medical fluid comprises:

0.02 to 0.1 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is (12-20): 1; the second liquid medicine comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

1.4 to 1.8 percent of sodium chloride;

the balance of water;

wherein the mass ratio of the first liquid medicine to the second liquid medicine is 1-1;

the mixed liquid medicine comprises:

0.01 to 0.05 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.09 percent of citric acid;

0 to 0.45 percent of sodium citrate;

0.7 to 0.9 percent of sodium chloride;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is 1:1 to 6;

the above units are mass percentages.

In a further technical scheme, the pH value of the first liquid medicine is 3.0-5.0.

In a further technical scheme, the pH value of the mixed liquid medicine is 6.0-6.7.

In a further technical scheme, the osmolality of the mixed liquid medicine is 260-320 mOsm.

In a further aspect, the first chamber or the second chamber further has an outflow opening that is held normally closed by a cover.

According to the technical scheme, the first cavity and the second cavity are arranged in tandem along the length direction of the container, and the sealing structure between the two cavities is achieved through ultrasonic plastic package welding.

In a further technical scheme, the first cavity and the second cavity are designed in a split mode; the sealing structure of the two cavities is destroyed by the temporary combination before use, so that the liquid medicine is mixed.

According to the further technical scheme, the temporary combination mode is that a needle-like structure arranged on one cavity punctures a sealing structure arranged on the other cavity.

In order to achieve the purpose, the technical scheme adopted by the invention in the method level is as follows:

a method for preparing a low-concentration atropine pharmaceutical product, which is characterized by comprising the following steps: the method comprises the following steps:

step one, preparing a first liquid medicine and a second liquid medicine;

the first liquid medicine comprises:

0.005-0.2% of active component;

0 to 3.5 percent of buffer system;

the balance of water;

the second liquid medicine comprises:

0 to 3.5 percent of buffer system;

0 to 5 percent of osmotic pressure regulator;

the balance of water;

the mixed liquid medicine of the first liquid medicine and the second liquid medicine comprises:

0.005-0.2% of active component;

0 to 3.5 percent of buffer system;

0 to 5 percent of osmotic pressure regulator;

the balance of water;

the above units are mass percentages;

step two, filtering the first liquid medicine and the second liquid medicine through filter membranes with the pore diameter less than or equal to 0.2 mu m respectively, and subpackaging the filtered first liquid medicine and the filtered second liquid medicine into two liquid storage tanks;

step three, filling the first liquid medicine into a hose;

step four, plastic packaging the hose in a row to enable the hose to form two independent cavities, and plastic packaging the first liquid medicine in the first cavity;

step five, filling a second liquid medicine into a second cavity of the hose;

and step six, carrying out plastic package on the second cavity, and carrying out plastic package on the second liquid medicine in the second cavity.

According to a further technical scheme, in the step one, the active ingredient comprises atropine or pharmaceutically acceptable salt thereof; the buffer system is one or more selected from citric acid, sodium citrate, boric acid, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate.

In a further technical scheme, in the first step, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and glucose.

According to a further technical scheme, the hose is made of polyolefin materials. The polyolefin material may be low density polyethylene, polypropylene, cyclic polyolefin resin, and composite layer materials comprising the above polyolefins.

In a further aspect, in the first step, the first chemical solution includes:

0.02 to 0.1 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is 12-20: 1;

the second medical fluid comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

1.4 to 1.8 percent of sodium chloride;

the balance being water.

In a further technical scheme, the mass ratio of the first liquid medicine to the second liquid medicine is 0.8-1:1.

According to the technical scheme, the first cavity and the second cavity are arranged in tandem along the length direction of the hose, and the sealing structure between the two cavities is achieved through ultrasonic plastic package welding.

According to a further technical scheme, in the fourth step and the sixth step, the ultrasonic plastic package adopts an ultrasonic generator with the model number of EDG-2020, the amplitude is 10-45%, and the plastic package time is 0.19-1.1 s.

According to the further technical scheme, when the device is used, the plastic package structure between the first cavity and the second cavity is damaged, so that the first liquid medicine and the second liquid medicine are mixed; after being mixed evenly, the pH value of the mixed liquid medicine is 6.0 to 6.7, and the osmotic pressure is 280 to 320mOsm.

In a further technical scheme, the first cavity and the second cavity are designed in a split mode; one cavity is provided with a puncture structure similar to a needle head; the other cavity is provided with a sealing structure which can be damaged by puncture.

The working principle and the advantages of the invention are as follows:

the invention relates to a low-concentration atropine drug product, which comprises a packaging container with two cavities, wherein the first cavity and the second cavity are in a communicated sealing design; the first liquid medicine is placed in the first cavity, and the second liquid medicine is placed in the second cavity; when the medical liquid mixing device is used, the double cavities are communicated by destroying the sealing structure between the first cavity and the second cavity, so that the first medical liquid and the second medical liquid are mixed into a mixed medical liquid; the mixed liquid medicine comprises: 0.005-0.2% of active component; 0 to 3.5 percent of buffer system; 0 to 5 percent of osmotic pressure regulator; the balance being water.

The invention combines the atropine with low concentration (without preservative) and a novel packaging container for use, the main drug end only contains the atropine and buffer solution, the diluting end contains the buffer solution and osmotic pressure regulator, and the main drug solution and the diluting solution are uniformly mixed when in use, thereby not only ensuring the stability of the atropine with low concentration, but also ensuring the sterility and comfort of use.

The advantages of the invention include:

1. the atropine concentration in the invention is lower (0.01-0.05%), compared with the existing product with concentration of 1%, the atropine can reduce the adverse reaction after being used by teenagers;

2. the invention has no preservative, and can reduce the side effect after use compared with the prior art;

3. compared with the existing common package, the novel double-cavity packaging container disclosed by the invention is used, so that the stability of atropine is ensured, and the sterility and the comfort of use are also ensured.

Drawings

FIG. 1 is a schematic illustration of a product container of an embodiment of the present invention with the chambers not in communication;

FIG. 2 is a schematic diagram of a product container according to an embodiment of the present invention with the chambers in communication;

FIG. 3 is a schematic illustration of a dual chamber separation arrangement for a product container according to an embodiment of the present invention.

In the above drawings: 1. a first chamber; 2. a second chamber; 3. a sealing structure; 4. an outflow port; 5. sealing the cover; 6. sealing the film; 7. a puncture tube; 8. a protective sleeve; 9. a protective cover.

Detailed Description

The invention is further described below with reference to the following figures and examples:

the present disclosure will be described more fully hereinafter with reference to the accompanying drawings, in which embodiments of the disclosure may be shown and described, and which, when modified and varied by the techniques taught herein, can be made by those skilled in the art without departing from the spirit and scope of the disclosure.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. The singular forms "a", "an", "the" and "the", as used herein, also include the plural forms.

The terms "first," "second," and the like, as used herein, do not denote any order or importance, nor do they denote any order or importance, but rather are used to distinguish one element from another element or operation described in such technical terms.

As used herein, the terms "comprising," "including," "having," and the like are open-ended terms that mean including, but not limited to.

As used herein, the term (terms), unless otherwise indicated, shall generally have the ordinary meaning as commonly understood by one of ordinary skill in the art, in this written description and in the claims. Certain words used to describe the disclosure are discussed below or elsewhere in this specification to provide additional guidance to those skilled in the art in describing the disclosure.

Example (b): a low concentration atropine drug product, as shown in figure 1, comprises a packaging container with two cavities, and a first cavity 1 and a second cavity 2 are of a communicable sealed design.

The medical liquid medicine injection device further comprises a first medical liquid arranged in the first cavity 1 and a second medical liquid arranged in the second cavity 2.

When the medical liquid mixing device is used, as shown in fig. 2, the double cavities can be communicated by breaking the sealing structure 3 between the first cavity 1 and the second cavity 2, so that the first medical liquid and the second medical liquid are mixed into a mixed medical liquid. The breaking means is many, and the sealing structure 3 can be broken by pressing in the case of the conventional one-piece dual chamber container.

The mixed liquid medicine comprises:

0.005-0.2% of active component; (0.005 or more but 0.2% or less)

0 to 3.5 percent of buffer system; (greater than 0 but 3.5% or less)

0 to 5 percent of osmotic pressure regulator; (greater than 0 but not more than 5%)

The balance of water;

the above units are mass percentages.

Preferably, the active ingredient comprises atropine or a pharmaceutically acceptable salt thereof, such as atropine sulfate.

The buffer system is selected from one or more of citric acid, sodium citrate, boric acid, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate. The osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and glucose.

Preferably, the mixed chemical solution includes:

0.005-0.2% of atropine or pharmaceutically acceptable salt thereof;

0 to 0.09 percent of citric acid;

0 to 0.45 percent of sodium citrate;

0 to 0.9 percent of sodium chloride;

the balance of water;

the above units are mass percentages.

Preferably, the first chemical solution includes:

0.01 to 0.4 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

the second liquid medicine comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

0 to 1.8 percent of sodium chloride;

the balance of water;

the above units are mass percentages;

wherein the mass ratio of the first liquid medicine to the second liquid medicine is 0.8-1: 1.

preferably, the first chemical solution includes:

0.02 to 0.1 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is (12-20): 1;

the second liquid medicine comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

1.4 to 1.8 percent of sodium chloride;

the balance of water;

the mixed liquid medicine comprises:

0.01 to 0.05 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.09 percent of citric acid;

0 to 0.45 percent of sodium citrate;

0.7 to 0.9 percent of sodium chloride;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is 1:1 to 6;

the above units are mass percentages.

Preferably, the pH of the first chemical solution is 3.0 to 5.0, preferably 4.0. The pH of the mixed liquid medicine is 6.0-6.7, preferably 6.1-6.7.

Preferably, the osmolality of the mixed drug solution is 260 to 320mOsm.

Preferably, the first chamber 1 or the second chamber 2 also has an outflow opening 4, which outflow opening 4 is kept normally closed by a cover 5.

Preferably, the first cavity 1 and the second cavity 2 are arranged in tandem along the length direction of the container, and the sealing structure 3 between the two cavities can be achieved through ultrasonic plastic package welding.

Alternatively, as shown in fig. 3, in another embodiment of the container, the first chamber 1 and the second chamber 2 are designed in a split manner, and the sealing structure of the two chambers is broken in a temporary combination manner before use, so that the liquid medicines are mixed. The temporary combination mode is that a needle-like structure arranged on one cavity punctures a sealing structure arranged on the other cavity.

Specifically, the front end of the first chamber 1 is provided with an outflow port 4, the outflow port 4 is kept normally closed by a sealing cover 5, and the rear end is provided with a sealing membrane 6.

The front end of the second cavity 2 is provided with a puncture tube 7, and the puncture tube 7 is communicated with the inside of the second cavity 2; when the mixing device is used, the sealing film 6 at the rear end of the first cavity 1 is punctured through the puncture tube 7 of the second cavity 2, so that the content in the second cavity 2 enters the first cavity 1 and is mixed with the content in the first cavity 1.

Preferably, the sealing film 6 corresponding to the rear end of the first cavity 1 is further provided with a protective sleeve 8, and the protective sleeve 8 is detachably combined with the rear end of the first cavity 1.

Preferably, the puncture tube 7 is kept sealed normally closed by a protective cap 9.

Preferably, the first chamber 1 is made of a flexible material or a hard material, and the second chamber 2 is made of a flexible material, so as to perform the pressing operation.

As shown in fig. 1 and 2, the preparation method of a low-concentration atropine pharmaceutical product is explained as follows:

the preparation method comprises the following steps:

step one, preparing a first liquid medicine and a second liquid medicine by mixing and stirring;

the first liquid medicine comprises:

0.005-0.2% of active component;

0 to 3.5 percent of buffer system;

the balance of water;

the second liquid medicine comprises:

0 to 3.5 percent of buffer system;

0 to 5 percent of osmotic pressure regulator;

the balance of water;

0.005-0.2% of active component;

0 to 3.5 percent of buffer system;

0 to 5 percent of osmotic pressure regulator;

the balance of water;

the above units are mass percentages.

Preferably, the active ingredient comprises atropine or a pharmaceutically acceptable salt thereof;

the buffer system is selected from one or more of citric acid, sodium citrate, boric acid, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate;

the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and glucose.

And step two, filtering the first liquid medicine and the second liquid medicine through filter membranes with the pore diameter of less than or equal to 0.2 mu m respectively, and subpackaging the filtered first liquid medicine and the filtered second liquid medicine into two liquid storage tanks.

And step three, filling the first liquid medicine in the first liquid storage tank into a hose, wherein the filling amount is about 0.5ml.

And step four, performing plastic packaging (such as ultrasonic plastic packaging and thermoplastic packaging) on the hose to enable the hose to form two independent cavities, and performing plastic packaging on the first liquid medicine in the first cavity 1.

And step five, filling the second liquid medicine in the second liquid storage tank into the second cavity 2 of the hose, wherein the filling quantity is about 0.5ml.

And step six, carrying out plastic package on the second cavity 2, and carrying out plastic package on the second liquid medicine in the second cavity 2.

Preferably, the hose is composed of a polyolefin material, such as low density polyethylene, polypropylene, cyclic polyolefin resin, and a composite layer material comprising the above polyolefin.

Preferably, in the fourth step and the sixth step, the plastic packaging is ultrasonic plastic packaging, the plastic packaging adopts an ultrasonic generator with the model number of EDG-2020, the amplitude is 10-45%, and the plastic packaging time is 0.19-1.1 s. Through ultrasonic plastic package, not only can the required plastic package effect be realized, but also the adverse effect of the heating of conventional thermal plastic package on the medicine can be avoided.

Wherein the mass ratio of the first liquid medicine to the second liquid medicine is 0.8-1:1, preferably 1:1.

when the device is used, the plastic package structure between the first cavity and the second cavity is damaged, so that the first liquid medicine and the second liquid medicine are mixed; after being mixed evenly, the pH value of the mixed liquid medicine is 6.0 to 6.7, and the osmotic pressure is 280 to 320mOsm.

To illustrate the practical technical effects of the present invention, the following test data are used for illustration:

table 1 shows the first result of the investigation of the influence factors of the main drug component (first drug solution)

As can be seen from table 1, the stability of the main drug terminals is shown as follows:

under the condition of pH4.0, the concentration characters, pH and osmolality have no obvious difference, the related substances are slightly increased under the conditions of 40 ℃ and acceleration (40 +/-2 ℃/25% RH), the impurity growth trend is more obvious as the concentration is lower, but the related substances all accord with the quality standard of the product, and the stability is good.

Table 2 shows the stability-content table of the main drug ingredient (first drug solution) under different pH conditions, wherein atropine is 0.1% in concentration.

pH value	Day 0	Illuminating for 8 days	Illuminating for 15 days	898.3 days at 40 deg.C	At 40 ℃ for 15 days
						1.0	100.0	99.9	99.4	98.3	97.6
3.0	99.6	99.1	98.0	100.0	99.8
						4.0	100.0	95.7	92.7	100.0	99.9
5.0	100.0	96.4	92.6	99.8	99.7
						5.6	100.0	95.5	92.4	99.5	98.9
6.0	100.0	97.7	95.3	99.9	99.4
						6.6	100.0	97.5	95.3	99.7	99.4
7.0	100.0	94.3	94.9	94.3	80.8
						8.0	93.3	80.0	/	42.1	/
9.0	75.0	11.7	/	0.0	/
						10.0	20.5	0.0	/	0.0	/

From table 2, it can be seen that the stability of the first liquid medicine (raw material medicine) at different pH values is stable under acidic conditions, i.e. pH 3.0-5.0, and the first liquid medicine needs to be protected from light.

Table 3 shows the second result of examining the influence factors of the main ingredient (first liquid)

As can be seen from Table 3, when the concentration of API is 0.02%, there is no significant difference in properties, pH, osmolality, etc. at pH 3.5-4.5, and the related substances are slightly increased at 40 ℃ and under acceleration conditions, but all meet the quality standards, so the product is stable at pH 3.5-4.5.

Table 4 shows the influence of the ratio of citric acid and sodium citrate in the main ingredient (first liquid medicine) on pH

As can be seen from Table 4, the amounts of citric acid and sodium citrate will affect the pH of the product, and to meet the pH 3.5-4.5, citric acid is required: sodium citrate is in the ratio of 8:1 to 24.5:1.

table 5 shows the results of examining the influence factors of the diluting end (second liquid medicine)

As can be seen from table 5, the pH and osmolality of the diluted end were not significantly different under each condition, and the diluted end was stable.

Table 6 shows the results of examining the stability of the mixed drug solutions at room temperature

As can be seen from Table 6, the pH, osmolality and content of the mixed liquid medicine have no obvious difference within 7 days at room temperature and 6.0-6.5, and related substances have a slight growth trend with time but are far below the limit requirement.

Table 7 shows the effect of the ratio of citric acid and sodium citrate in the mixed solution on pH

As is clear from table 7, the amounts of citric acid and sodium citrate used affect the pH of the mixed drug solution, so that when API is 0.05% and sodium chloride is 0.85%, citric acid is required to satisfy the conditions of pH6.0 to 6.5: sodium citrate is added in the ratio of 1:1 to 1:6.

table 8 shows the effect of the amount of NaCl in the mixed solution on the osmolality

As can be seen from table 8, the amount of sodium chloride used affected the osmolality of the liquid drug mixture, and was 0.05% in API, 0.05% in citric acid: sodium citrate is 1:2, the dosage of the sodium chloride in the mixed liquid medicine is 7-9 mg/ml, and the dosage of the sodium chloride is 14-18 mg/ml.

Wherein, in tables 1, 3 and 6, the molecular formula of the impurity C is C ₉ H ₁₀ O ₃ Molecular weight 166.17, commonly known as alpha-hydroxymethylphenylacetic acid; the molecular formula of the impurity A is C ₁₇ H ₂₁ NO ₂ Molecular weight 271.35, commonly known as (1R, 3r, 5S) -8-methyl-8-azabicyclo [3.2.1]Octyl-3-yl 2-phenyl acrylate; impurities A and C are degradation impurities, are controlled as specific impurities and can reflect the purity of atropine and the stability condition of the atropine in a preparation.

The invention provides a preparation method for combining a low-concentration atropine composition with a novel package, and compared with the prior art, the preparation method provided by the invention overcomes the problems of high drug concentration, poor stability and the like of the existing commercially available preparation. The invention optimizes the prescription, adopts a novel packaging container, and the prepared product not only meets the use requirement, but also has simple and controllable preparation process, thereby reducing the cost.

The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A low concentration atropine pharmaceutical product characterized by:

the method comprises the following steps:

further comprising:

the mixed liquid medicine comprises:

0.005 to 0.2 percent of active ingredients;

0 to 3.5 percent of a buffer system;

osmotic pressure regulator 0~5%;

the balance of water;

the above units are mass percentages.

2. The pharmaceutical product according to claim 1, wherein: the active ingredient comprises atropine or a pharmaceutically acceptable salt thereof;

the buffer system is one or more selected from citric acid, sodium citrate, boric acid, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate.

3. The pharmaceutical product according to claim 1, wherein: the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and glucose.

4. The pharmaceutical product according to claim 1, wherein:

the mixed liquid medicine comprises:

0.005 to 0.2 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.09 percent of citric acid;

0 to 0.45 percent of sodium citrate;

0 to 0.9 percent of sodium chloride;

the balance of water;

the above units are mass percentages.

5. The pharmaceutical product according to claim 1 or 4, characterized in that:

the first liquid medicine comprises:

0.01 to 0.4 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

the second liquid medicine comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

0 to 1.8 percent of sodium chloride;

the balance of water;

the above units are mass percentages;

wherein the mass ratio of the first liquid medicine to the second liquid medicine is 0.8 to 1:1.

6. the pharmaceutical product according to claim 1 or 4, characterized in that:

the first liquid medicine comprises:

0.02 to 0.1 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is 12 to 20:1;

the second liquid medicine comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

1.4 to 1.8 percent of sodium chloride;

the balance of water;

wherein the mass ratio of the first liquid medicine to the second liquid medicine is 1~1;

the mixed liquid medicine comprises:

0.01 to 0.05 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.09 percent of citric acid;

0 to 0.45 percent of sodium citrate;

0.7 to 0.9 percent of sodium chloride;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is 1:1~6;

the above units are mass percentages.

7. The pharmaceutical product according to claim 1, wherein: the pH value of the first liquid medicine is 3.0-5.0.

8. The pharmaceutical product according to claim 1, wherein: the pH value of the mixed liquid medicine is 6.0 to 6.7.

9. The pharmaceutical product according to claim 1, wherein: the osmolality of the mixed liquid medicine is 260 to 320mOsm.

10. The pharmaceutical product according to claim 1, wherein: the first chamber or the second chamber also has an outflow opening which is kept normally closed by a cover.

11. The pharmaceutical product according to claim 1, wherein: the first cavity and the second cavity are arranged in tandem along the length direction of the container, and the sealing structure between the two cavities is formed by ultrasonic plastic package welding.

12. The pharmaceutical product according to claim 1, wherein: the first cavity and the second cavity are designed in a split mode; the sealing structure of the two cavities is destroyed by means of temporary combination before use, so that the liquid medicines are mixed.

13. The pharmaceutical product according to claim 12, wherein: the temporary combination mode is that a needle-like structure arranged on one cavity punctures a sealing structure arranged on the other cavity.

14. A method for preparing a low-concentration atropine pharmaceutical product, which is characterized by comprising the following steps: the method comprises the following steps:

step one, preparing a first liquid medicine and a second liquid medicine;

the first liquid medicine comprises:

0.005 to 0.2 percent of active ingredient;

0 to 3.5 percent of buffer system;

the balance of water;

the second liquid medicine comprises:

0 to 3.5 percent of buffer system;

osmotic pressure regulator 0~5%;

the balance of water;

0.005 to 0.2 percent of active ingredients;

0 to 3.5 percent of a buffer system;

osmotic pressure regulator 0~5%;

the balance of water;

the above units are mass percentages;

step three, filling the first liquid medicine into a hose;

step five, filling a second liquid medicine into a second cavity of the hose;

15. The method of claim 14, wherein: in step one, the active ingredient comprises atropine or a pharmaceutically acceptable salt thereof;

16. The method of claim 14, wherein: in step one, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol and glucose.

17. The method of claim 14, wherein: the hose is composed of a polyolefin material.

18. The method of claim 14, wherein: the first chamber or the second chamber also has an outflow opening which is kept normally closed by a cover.

19. The method of claim 14, wherein:

in the first step, the first chemical solution includes:

0.02 to 0.1 percent of atropine or pharmaceutically acceptable salt thereof;

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

the balance of water;

wherein the mass ratio of the citric acid to the sodium citrate is 12 to 20:1;

the second liquid medicine comprises:

0 to 0.18 percent of citric acid;

0 to 0.9 percent of sodium citrate;

1.4 to 1.8 percent of sodium chloride;

the balance being water.

20. The method of claim 14, wherein: the mass ratio of the first liquid medicine to the second liquid medicine is 0.8 to 1.

21. The method of claim 14, wherein: the first cavity and the second cavity are arranged in tandem along the length direction of the hose, and the sealing structure between the two cavities is formed by ultrasonic plastic package welding.

22. The method of claim 14, wherein: in the fourth step and the sixth step, the plastic packaging is ultrasonic plastic packaging, the plastic packaging adopts an ultrasonic generator with the model number of EDG-2020, the amplitude is 10 to 45 percent, and the plastic packaging time is 0.19 to 1.1s.

23. The method for producing as claimed in claim 14, wherein: when the device is used, the plastic package structure between the first cavity and the second cavity is damaged, so that the first liquid medicine and the second liquid medicine are mixed; after being mixed evenly, the pH value of the mixed liquid medicine is 6.0 to 6.7, and the osmotic pressure is 280 to 320mOsm.

24. The method of claim 14, wherein: the first cavity and the second cavity are designed in a split mode; one cavity is provided with a puncture structure similar to a needle head; the other cavity is provided with a sealing structure which can be damaged by puncture.